Inhalers and Related Methods

ABSTRACT

An inhaler housing (14) for an inhaler (10) for inhaling inhalable substances, the inhaler having: a body (14) and a dose counter (24) with a return spring (28), wherein a distinct guide surface (162) is provided for guiding the end of the return spring into a recess (152), the distinct guide surface being wider than an entrance mouth (160) of the recess, a dose counter chamber (22) being provided which is separated from a tubular interior space (182) of the inhaler by a barrier (180), the barrier including a stepped upper wall area (184) including at least three steps (186, 188, 190, 192) at different levels, the inhaler having a valve stem block (62) having an inner bore and a valve stem block having a seal (224) in the inner bore with a second diameter which is smaller than a first diameter of the inner bore, the inhaler having a canister (150) being adapted to move during operation between 1 and 4 mm, a drive being arranged to apply a firing force of between 15N and 60N of force to the canister at a position of the canister relative to a valve stem (54) at which the canister fires.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of Application No.GB1702407.6, filed Feb. 14, 2017, which application is incorporated byreference herein, in its entirety and for all purposes.

FIELD OF THE INVENTION

The present invention relates to inhalers, including breath actuated andmetered dose inhalers. The invention relates to oral and nasal inhalers.The invention also relates to methods of metering inhalable substancesin metering valves of canisters for medicament inhalers, inhalerhousings and inhaler valve stem and valve stem block interfaces.

BACKGROUND OF THE INVENTION

A known inhaler, which is a breath actuated inhaler, has a pressurisedcanister and a metering valve for controlling the ejection of inhalablesubstances from the canister. The canister is operable by a forceholding unit having a cap housing attachable to a main housing of theinhaler. The metering valve includes a valve stem for transferringsubstances from an interior reservoir of the canister into the meteringchamber and then out of the metering chamber along the valve stem in thedirection of a nozzle of the inhaler. A radially directed capillary portis provided in the valve stem for communicating substances out of theinterior reservoir for communication along the valve stem to themetering chamber and a similar port is provided for communicatingsubstances out of the metering chamber and along the valve stem towardsthe nozzle. In use, a mouthpiece cap is opened to ready the inhaler forinhalation and then after inhalation the mouthpiece cap is closed andresets a canister fire system. It has been found that the inhaler can beleft after inhalation with the mouthpiece dust cap in the openedposition with the metering chamber communicating with atmosphere via thevalve stem and nozzle. This can result in the variance of activeingredients in at least one subsequent dose. This means that users willsometimes remove a force holding unit cap housing from the main body ofthe inhaler and try to ensure that the metering chamber is sufficientlyprimed by firing a number of doses and this is both wasteful and mayresult in damage to the inhaler.

In some inhalers, when it is necessary to make changes to internalcomponents, it is difficult to provide space and good guidance for allthe necessary interior moving parts. Also, the assembly of some inhalerdose counters can be difficult.

Furthermore, in some inhalers, despite a tight connection between thevalve stem and a valve stem block within the main body, blowback canoccur which is leakage of substances between the valve stem block andvalve stem. It can also be difficult in some inhalers to achievereliable dose counting to reflect the number of doses actually providedby the inhaler.

The present invention aims to alleviate at least to a certain extent atleast one of the problems of the prior art.

Alternatively, the present invention aims to provide a useful inhaler,method of metering substances in a metering valve of a canister for amedicament inhaler and/or useful inhaler parts.

SUMMARY OF THE INVENTION

According to one aspect, the present disclosure discloses an inhalerhousing for an inhaler for inhalable substances, the inhaler housingbeing arranged to contain a pressurised canister for sliding motionwithin a tubular body portion thereof, the inhaler housing having avalve stem block for connection to a valve stem of a pressurisedcanister, the valve stem block having a top surface, the tubular bodyportion having at least two mutually opposed guide ribs for guidingcanister position within the tubular body portion, the guide ribs havingsubstantially straight guide edges extending substantially parallel toand spaced from one another, each straight guide edge having an uppercorner where the straight guide edge meets a further surface of the ribleading outwardly towards an upper rib section near an inner wall of thetubular body portion, at least one of the ribs having its straight guideedge's upper corner positioned a distance D2 in a direction parallel toan axis of the valve stem block along away from the top surface of thevalve stem block, a distance between the straight guide edges of theribs perpendicular to the axis being ID2, and in which the ratio D2/ID2is less than 0.8.

It has been surprisingly found that ratios below this value enable veryefficient and smooth guidance of the canister relative to the inhalerhousing in some configurations.

The ratio D2/ID2 may be less than 0.75, about 0.7 being one example.

The further surface of at least one guide rib may extend away from thevalve stem block and terminate at a distance D3 from the top surface ofthe valve stem block in the direction parallel to the axis, the ratioD3/ID2 being less than 0.9 or less than 0.85, about 0.8 being oneexample.

Each guide rib meets the upper rib section near the inner wall of thetubular body portion at outer rib positions wherein the outer ribpositions are a distance ID1 apart in a direction perpendicular to theaxis, and in which the ratio ID2/ID1 is between 0.7 and 0.9, typicallybetween 0.75 and 0.85, about 0.78 or 0.8 being two examples.

According to a further aspect, the present disclosure discloses aninhaler housing for an inhaler for inhaling inhalable substances, theinhaler having: a body and a dose counter with an actuation memberadapted to drive a dose indication portion of the dose counter against areturn spring, the body including a recess for location of an end of thereturn spring; the recess having a substantially flat reaction surface,a shoulder surface adjacent the reaction surface and an entrance mouthinto the reaction surface; wherein a distinct guide surface is providedfor guiding the end of the return spring into the recess, the distinctguide surface being wider than the entrance mouth in a direction acrossthe mouth.

This feature of the distinct guide surface being wider than the entrancemouth advantageously assists in assembly of the dose counter into theinhaler since when the return spring is being fitted as part of the dosecounter installation it can slide along the distinct guide surfacerelatively easy into the recess.

The entrance mouth may have at least one chamfered entrance lip, thedistinct guide surface having a slanted edge which is an extension ofthe lip.

The distinct guide surface may be substantially planar. The distinctguide surface may have an edge which intersects with an adjacent curvedsurface of the body.

At least a portion of the distinct guide surface may comprise a portionof the body which is recessed relative to an adjacent portion of thebody.

A further aspect of the present disclosure discloses an inhaler housingfor an inhaler for inhaling inhalable substances, the inhaler housinghaving a tubular portion defining a tubular interior space forcontaining a pressurised canister containing inhaler substances, a valvestem block for engagement with a valve stem of such a pressurisedcanister, and a dose counter chamber for containing a dose counterassembly, the dose counter chamber being separated from the tubularinterior space by a barrier, the barrier including a stepped upper wallarea including at least three steps at different levels.

This configuration advantageously permits enough room for the dosecounter in the dose counter chamber and enough room for the movableparts inside the inhaler housing including the pressurised canister andin at least one arrangement has been found to be particularly effectivein space saving.

The inhaler may include four said steps.

The steps may be arcuate.

The arcuate steps may have substantially flat areas alignedsubstantially perpendicular to an axis of the valve stem block as wellas part-cylindrical riser surfaces between the substantially flat areas.

The steps may be substantially concentric with an axis of the valve stemblock.

The steps may extend around the valve stem block a distance of about 180degrees.

The material forming the barrier may be of substantially constantthickness substantially throughout the steps.

The dose counter chamber may be formed with at least one heat stakingpin for mounting of a dose counter system, the heat staking pin beingdirectly attached to at least two of the steps.

The heat staking pin may be attached to at least one step surface thatis oriented substantially perpendicular to an axis of the valve stemblock and to at least one and preferably two step risers.

An aperture for a drive pin for actuating the dose counter may be formedthrough a second furthest step away from the valve stem block.

According to a further aspect, the present disclosure discloses aninhaler valve stem and valve stem block interface for a breath actuatedinhaler having a dose counter, a pressurised canister containing inhalersubstances including a medicament, which may be in solution orsuspension, the valve stem block having a cylindrical inner bore with aninner diameter which is a first diameter, the cylindrical inner borebeing for accepting a valve stem with an outer diameter, the valve stemblock having a seal in the inner bore with a second diameter which issmaller than the first diameter.

It has been found with this configuration that, surprisingly, bettersealing is achieved than with a simple interference fit between acylindrical outer wall of a valve stem and a cylindrical inner wall of avalve stem block with a larger interference fit. This new configurationhas been found to be particularly effective at sealing and avoidingblowback leakage. Especially with regard to the dose counter, the sealpermits a relatively low insertion force to be needed to insert thevalve stem into the valve stem block and enables very accuratepositioning of the valve stem relative to the valve stem block in anaxial direction of the valve stem, while at the same time providing asurprisingly effective seal bearing in mind the low insertion force.

The first diameter may be about 3.22 mm.

The first diameter may be about 3.5% larger than the second diameter.

An outer diameter of the valve stem may be smaller than the firstdiameter but larger than the second diameter prior to introduction ofthe valve stem into the inner bore, preferably about 0.75% to 1.5%larger, for example about 1% larger.

The valve stem block may include an annular recess concentric with andextending around the inner bore at least partially around thecircumference thereof, the inner diameter of the annular recess beingabout 25 to 50% larger than the inner diameter of the cylindrical innerbore, for example about 40% larger.

The seal may be inwardly convex.

The seal may have an inner surface which is part of a toroid.

The seal may be located at or near an entrance to the inner bore.

The seal may be formed integrally with, e.g. of the same material as,the material defining the inner bore which may, for example, be mouldedplastics.

A further aspect of the present disclosure discloses a breath actuatedinhaler having a drive adapted to drive a pressurised canister so as toretract a metering valve stem into the canister to fire the canister,the canister being adapted to move during operation between 1 and 4 mmbetween end positions of its length of travel relative to the valvestem, the drive being arranged to apply a firing force of between 15Nand 60N of force to the canister at a position of the canister relativeto the valve stem at which the canister fires.

With this configuration of drive and canister travel, it has beensurprisingly found possible to have very accurate and reliable firing ofthe canister, as well as accurate counting when a dose counter isprovided. Furthermore, a long extent of travel of the canister toretract the valve stem can be provided to ensure that both count andfire very reliably occur.

The drive may comprise a drive spring.

The canister may be arranged to move between 1 and 3 mm between the endpositions. In one example the movement between the end positions is 3mm.

The drive may be adapted to provide the firing force as more than 40N,preferably also less than 60N.

The drive may be adapted to provide the firing force as more than 35N.

The firing force may be greater than the sum at the point of firing ofopposing forces applied to the canister by a valve stem spring in thecanister and a return spring for an actuator pin of a dose counter ofthe inhaler.

A further aspect of the present disclosure discloses a breath actuatedinhaler having a main body for accommodating a medicament reservoir, acanister fire system for moving the canister to release a dose inresponse to air flow, a cap housing for enclosing the canister firesystem and canister within an interior chamber defined by the main bodyand the cap housing, wherein a lock system is provided for locking thecap housing on the main body.

Advantageously, a user can be prevented from tampering with and damagingthe interior components of the inhaler. In the case of a breath actuatedinhaler, this is particularly advantageous because prior inhalers haverequired the ability to remove the cap housing for manual priming of themetering chamber. But, when a metering valve is provided with an openingconfigured to permit flow in a direction with an axial component alongthe valve stem directly between the transfer space inside the valve stemand the interior reservoir, and when the interior reservoir is arrangedfor orientation above the metering chamber whereby gas such as airlocated within the metering chamber is replaced with liquid from theinterior reservoir, it is no longer necessary to be able to open theinhaler for manual priming of the metering chamber by manually pushingand firing the canister.

Helical threads may be provided for rotational attachment of the caphousing on the main body and for resisting relative longitudinalmovement therebetween without rotation.

The lock system may include a protrusion in the region of a helicalthread on one of the main body and the cap housing which is lockable ina recess in the region of a helical thread on the other of the main bodyand the cap housing.

Two said protrusions may be engageable in two said recesses formed atopposing locations on the inhaler.

Each protrusion may have a leading ramp surface and a trailing rampsurface, the included angle between the ramp and trailing surfaces beingabout 95° to 120°; the included angle of the protrusion preferably beinglarger than that of the recess.

The main body may have a central axis and the ramp surfaces are inclinedat an angle of about 45° plus or minus 15° (or plus or minus 10°) totangential.

The lock system may include a first lock member on one of the main bodyand the cap housing which is adapted to engage a second lock member at alock interface formed by respective engagement faces thereof, the lockinterface being oriented substantially perpendicular to tangential.

The main body may have a central axis and the first lock member has aradial extent of 0.25 to 0.75 mm, preferably about 0.35 to 0.45 mm; thefirst lock member preferably having a longitudinal extent of about 10mm.

The main body and the cap housing may be formed of plastics material andthe lock system may be configured so that a release torque required toovercome the locking provided by the plastics main body and cap housingis more than 1 Nm.

The lock system may be configured such that the release torque isbetween 2 and 5 Nm, preferably between 2.5 and 3 Nm, about 2.7 Nm beingone example.

The present disclosure discloses in another aspect a method of meteringinhalable substances in a metering valve of a canister for a medicamentinhaler, the method comprising: providing the metering valve with ametering chamber and valve stem extending from a metering chamber to aninterior reservoir of the canister, with the valve stem defining acommunication path between the metering chamber and the interiorreservoir, the communication path including an opening configured topermit flow between a transfer space inside the valve stem and theinterior reservoir; and orienting the interior reservoir above themetering chamber and replacing gas such as air located within themetering chamber with liquid from the interior reservoir.

The present inventors have worked out that the reasons why inaccuratedosing can occur include that when the metering chamber is left ventedto atmosphere in some prior inhalers for as little as 2 minutes, a gasor air lock can form in the metering chamber and when the meteringchamber is next connected for communication with the interior reservoir,due to the radial capillary port, the gas or air is trapped within themetering chamber and liquid does not enter the metering chamber reliablyas the next dose. The air may enter the metering chamber from theatmosphere in the prior art. This may happen as propellant in themetering chamber evaporates and diffuses into the atmosphere. Using thepresently disclosed method which involves the use of the openingconfigured to permit flow in a direction with an axial component alongthe valve stem directly between a transfer space inside the valve stemand the interior reservoir, when the interior reservoir is orientedabove the metering chamber, this enables liquid from the interiorreservoir to replace gas such as air located within the metering chamberand an accurate dose can be administered at the next dose.

The opening may be configured to permit flow in a direction with anaxial component along the valve stem directly between the transfer spaceinside the valve stem and the interior reservoir.

The replacing gas located in the metering chamber with liquid from theinterior reservoir may include flowing liquid under pressure through theopening, along the valve stem to a portion of the communication pathcommunicating with the metering chamber.

The method may include flowing gas from the metering chamber, in adirection counter to a direction of liquid flow from the interiorreservoir, along the communication path into the interior chamber.

The method may include providing the opening as an elongated opening.

The method may include providing a second opening to the communicationpath diametrically opposed to the first said opening.

The method may include providing the valve stem with at least one saidopening into the interior reservoir as having an axially orientedopening portion which is oriented facing directly axially along alongitudinal axis of the valve stem into the interior reservoir, andwhich includes flowing liquid into the metering chamber via said axiallyoriented opening portion.

The method may include venting the metering chamber to atmosphere via avalve stem block and/or nozzle.

The method may include operating the metering valve and canister withina medicament inhaler and holding the valve stem depressed relative tothe canister with the metering chamber vented to atmosphere so as atleast partially to permit substances within the metering chamber tovaporise and to permit atmospheric air to enter the metering chamber.

Advantageously, the inhaler can be left for a long period such as 24hours with the metering chamber communicating with atmosphere and thenwhen the metering chamber is reconnected to the interior reservoir andthe interior reservoir is oriented above the metering chamber themetering chamber can fully fill with liquid for the next dose.Advantageously, in a breath actuated inhaler, the features of the methodmean therefore that any force holding unit and/or cap housing for theinhaler can be permanently secured or locked on to the inhaler so thatusers cannot tamper with the interior and there is no need to performmanual priming of the metering valve, which is a necessity in prior artinhalers, before the next dose is taken.

The method may include providing the medicament inhaler as a breathactuated inhaler, and may include, in response to air flow, firing thecanister by closing communication between the metering chamber andinterior reservoir and opening communication between the meteringchamber and atmosphere, the valve stem being held depressed afterfiring.

The method may include resetting the inhaler to a reset configurationwith a reset actuator so as to close communication between the meteringchamber and atmosphere and open communication between the meteringchamber and the interior reservoir, and carrying out the orienting ofthe interior reservoir above the metering chamber while the inhaler isin the reset configuration.

The method may include providing the reset actuator as a lever, pressbutton, hinged or rotatable piece, dust cap, nasal outlet cap ormouthpiece cap for the inhaler. Closing the actuator may reset theinhaler. In the case of an oral inhaler the reset actuator may be a dustcap mouthpiece cap. In the case of a nasal inhaler, the reset actuatormay take a variety of forms, including but not limited to a dust cap ora movable lever, cap or button. In this case, the carrying out of theorienting of the interior reservoir above the metering chamber beingcarried out once the reset actuator has been opened to a configurationsuitable for inhalation or otherwise operated. Therefore, it can beensured that right before inhalation, the metering chamber is full ofliquid and any gas which may have been in the metering chamber has beendrawn into the interior reservoir due to the free flowing communicationpathway between metering chamber and interior reservoir.

In an alternative embodiment, the inhaler may include a dust cap ormouthpiece cap which closes communication between the metering chamberand atmosphere but does not reset the inhaler. In these cases,optionally, a separate reset actuator may be provided.

The method may include providing the medicament inhaler as a metereddose inhaler and may include applying a force to the canister to holdthe valve stem depressed; and may include subsequently releasing thecanister to extend the valve stem and carrying out the orienting of theinterior reservoir above the metering chamber.

The method may include providing the inhalable substances as includingat least one propellant.

The method may include providing at least one said propellant as ahydrofluoroalkane, such as 1,1,1,2-tetrafluoroethane.

The method may include providing at least one said propellant with asurface tension at 25° C. of about 6 to 10 mN/m, typically about 7 to 9mN/m, about 8 mN/m being one example.

Advantageously, it has been found that fluid with this surface tensionis capable of avoiding gas or air lock in the metering chamber byflowing into the metering chamber when the features of the presentlydisclosed method are used.

The method may include providing the inhalable substances as includingan active ingredient in suspension or in solution, such asbeclomethasone dipropionate (BDP) or tiotropium bromide.

The present disclosure also discloses in another aspect a breathactuated inhaler for the inhalation of inhalable substances, the inhalercomprising: a canister having an interior reservoir containingpressurised inhalable substances including fluid; a metering valveincluding a metering chamber and a valve stem defining a communicationpath between the metering chamber and the interior reservoir, thecommunication path including an opening configured to permit flowbetween a transfer space inside the valve stem and the interiorreservoir, the interior reservoir being arranged for orientation abovethe metering chamber whereby gas such as air located within the meteringchamber is replaced with liquid from the interior reservoir.

Advantageously, with this configuration of metering valve there is noneed to manually prime the metering chamber by repeatedly firing thecanister manually and an accurate next dose can be provided to themetering chamber since a gas or air lock can be avoided. This alsomeans, advantageously, that in a breath actuated inhaler having a forceholding unit or cap housing secured to a main body of the inhaler, thesecomponents may be locked together so that it is relatively difficult fora user to remove the force holding unit or cap housing and tamper withthe interior components. Instead, there is no need to perform manualpriming and the inhaler main housing and the cap housing can bepermanently locked together enclosing the internal moving parts of theinhaler where they cannot easily be damaged.

The opening may be configured to permit flow in a direction with anaxial component along the valve stem directly between a transfer spaceinside the valve stem and the interior reservoir.

The communication path may be configured to permit liquid to flow underpressure along the communication path to the metering chamber and gas toflow in a reverse direction therealong from the metering chamber intothe interior reservoir.

The opening may comprise an elongated opening.

The inhaler may include a second opening or further openings into thecommunication path.

The second opening may be diametrically opposed to the first saidopening.

The valve stem may have at least one opening into the interior reservoirwith an axially oriented portion facing directly axially along alongitudinal axis of the valve stem into the interior reservoir for theflow of fluid directly into the communication path in an axial directionalong the valve stem.

The inhaler may include a metering chamber exit port for venting themetering chamber to atmosphere via a stem block and/or nozzle.

The inhaler may include a canister fire system for ejecting inhalablesubstances from the inhaler in response to air flow by closingcommunication between the metering chamber and the interior reservoirand opening communication between the metering chamber and atmosphere.The canister fire system preferably includes a drive such as a springfor driving the canister relative to the valve stem. The inhaler mayhave an actuator system for operating the drive, the actuator systemoptionally including a vacuum chamber having a vacuum release systemoperable to permit the drive to drive movement of the canister relativeto the valve stem. The vacuum release system may be air flow actuatable.

The actuator and/or drive may include or operate as a latch, trigger orswitch and may take other forms in other embodiments such as beingelectromechanical.

The canister fire system may be adapted to depress the valve stem intothe canister to cause inhalable substances to be ejected from theinhaler and to hold the valve stem depressed with the metering chambercommunicating with atmosphere.

The canister fire system may include a reset actuator which is operableso as to extend the valve stem relative to the canister in order toclose communication between atmosphere and the metering chamber and toopen communication between the metering chamber and the interiorreservoir.

In the case of a nasal inhaler, the reset actuator may, for example,comprise a dust cap or a lever, cap or button. In the case of an oralinhaler, the reset actuator may comprise a dust cap or mouthpiece capfor a mouthpiece of the inhaler. The mouthpiece cap may be closable topermit extension of the valve stem relative to the canister, themouthpiece cap optionally being hingedly connected to a main housing ofthe inhaler for camming engagement with at least one drive rod. Thedrive rod may be associated with a yoke for pushing on a drive elementto compress a spring of the drive.

In an alternative embodiment, the inhaler may include a dust cap ormouthpiece cap which closes communication between the metering chamberand atmosphere but does not reset the inhaler. In these cases,optionally, a separate reset actuator may be provided.

The inhaler may include a preventer adapted, after an inhalation hastaken place, to prevent a further inhalation until the reset actuatorhas been operated to extend the valve stem. In the case of a mouthpieceor other cap, this may comprise closing the cap.

Advantageously, the preventer may therefore ensure that the user closesthe cap at some time before each inhalation and this in turn means thatreliable dosing can be achieved.

The preventer may comprise a warning signaller, such as an audible orvisual alarm, dose counter or warning notice, quick reference guide orinstructions.

The inhaler may include inhalable substances in the interior reservoirwhich include at least one propellant.

At least one said propellant may comprise a hydrofluoroalkane, such as1,1,1,2-tetrafluoroethane.

At least one said propellant may have a surface tension at 25° C. ofabout 6 to 10 mN/m, typically about 7 to 9 mN/m, about 8 mN/m being onexample.

The inhaler may include at least one inhalable substance in the interiorreservoir as an active ingredient, for example in suspension or insolution, such as beclomethasone dipropionate or tiotropium bromide.

The inhaler may include a dose counter for counting doses, preferablyfor making one count with each inhalation of a dose.

The dose counter may include: (a) a tape bearing dose indicia fordisplaying counts and/or (b) an actuator pin for contact with thecanister, or a body movable therewith, for counting doses, andpreferably a dose counter chamber separated by a barrier from an innerspace of the inhaler for containing the canister, the actuator pinoptionally extending out of the dose counter chamber through an aperturein the wall for contact during counting with the canister (or the bodymovable therewith).

The inhaler may be a breath actuated inhaler.

The inhaler may be a metered dose inhaler.

The inhaler may be an oral inhaler.

The inhaler may be a nasal inhaler.

The inhaler may include a reset actuator which when actuated preventsexposure of the metering chamber to atmosphere, wherein the inhalerprovides 75 to 125% of labelled claim for a dose following exposure ofthe metering chamber to atmosphere for a time period which is more thanone minute.

In this case, the reset actuator may be a mouthpiece cap that, whenclosed, prevents exposure of the metering chamber to atmosphere.

The inhaler may provide 75 to 125% of labelled claim for a dosefollowing exposure of the metering chamber to atmosphere for a timeperiod which is more than two minutes.

The inhaler may provide 75 to 125% of labelled claim for a dosefollowing exposure of the metering chamber to atmosphere for a timeperiod which is one hour, more than one hour, 24 hours or more than 24hours.

Operation of the inhaler may include, subsequent to closing themouthpiece, opening the mouthpiece.

The inhaler may include a metering valve spring and an opposing canisterspring for drivingly firing the canister, the metering valve spring,canister spring and metering valve being arranged in the inhaler suchthat an equilibrium of various forces is achieved in at least oneready-to-fire configuration of the inhaler.

In that case, the operation of the inhaler may include at least onesuction force, e.g. provided by a pneumatic chamber; the suction forcepreferably operating against the canister spring.

In another aspect, the present application discloses use of a meteringvalve for preventing gas lock within a metering chamber of an inhalerhaving a pressurised canister, the metering valve having a meteringchamber and a valve stem extending from the metering chamber to aninterior reservoir of the canister, with the valve stem defining acommunication path between the metering chamber and the interiorreservoir, the communication path including an opening configured topermit flow between a transfer space inside the valve stem and theinterior reservoir, in use the interior reservoir being oriented abovethe metering chamber so as to cause movement through the opening and gassuch as air located within the metering chamber to be replaced withliquid from the interior reservoir.

The use may be performed in a breath actuated inhaler. The inhaler maybe oral. Nasal inhalers of this type are also envisaged.

The use may be performed in a metered dose inhaler. The metered doseinhaler may be oral or nasal.

When the present disclosure is implemented in a metered dose inhaler,this may comprise a press and breathe metered dose inhaler, for examplein which a canister is pushed by hand to fire, normally directlyalthough indirect operation is an alternative, normally using fingerand/or thumb operation of the canister.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be carried out in various ways and a number ofpreferred embodiments will now be described by way of example withreference to the accompanying drawings, in which:

FIGS. 1A and 1B show respective isometric views of a preferred inhaler;

FIG. 2 shows an exploded view of the inhaler shown in FIGS. 1A and 1B;

FIG. 3 is an enlarged view of the dose counter assembly shown in FIG. 2;

FIG. 4 is an isometric sectional view of a metering valve of the inhalerand part of the canister shown in FIG. 2;

FIGS. 5A, 5B, 5C and 5D show various details of the inhaler and parts ofit in a closed configuration thereof;

FIGS. 6A, 6B, 6C and 6D show various details of the inhaler in an openedconfiguration thereof;

FIGS. 7A, 7B, 7C and 7D show various details of the inhaler in anactuated configuration thereof;

FIGS. 8A, 8B, 8C and 8D show various details of the inhaler in a closingconfiguration thereof;

FIG. 9 schematically shows forces and ports within the inhaler in theclosed configuration of FIGS. 5A to 5D;

FIG. 10 schematically shows forces and ports within the inhaler in theopened configuration of FIGS. 6A to 6D;

FIG. 11 schematically shows forces and ports within the inhaler in theactuated configuration of FIGS. 7A to 7D;

FIG. 12 is a sectional elevational view of part of the inhaler shown inFIG. 1A with long dash lines denoting the top of ribs used in an earlierprototype;

FIG. 13 shows a portion of the inhaler of FIG. 1A with the dose counterand dose counter door removed;

FIG. 14A is a sectional isometric view of part of the inhaler shown inFIG. 1A;

FIG. 14B shows part of the inhaler with a dose counter not yetinstalled, showing heat stake pins;

FIGS. 15A and 15B show respective side elevation and isometric views ofthe valve stem block of the inhaler of FIG. 1A;

FIGS. 16A, 16B, 17A, 17B, 17C, 17D, 18A, 18B and 18C show various viewsof part of the inhaler, including components showing the interlockinginteraction of the main body of the inhaler with a cap housing thereof;

FIG. 19 shows a modified form of the inhaler of FIG. 1A in which theforce holding unit and cap housing are removed and the modified inhalertakes up the form of a metered dose inhaler; and

FIG. 20 shows a side view of the inhaler shown in FIG. 1A; and

FIG. 21 shows a comparative graph of delivered dose recovery at varioustime delays post previous actuation for the inhaler of FIG. 1A and aninhaler having a metering valve with radial capillary metering chamberinlet and outlet ports.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of embodiments of the inhaler andaccompanying methods will be better understood when read in conjunctionwith the appended drawings of exemplary embodiments. It should beunderstood, however, that the invention is not limited to the precisearrangements and instrumentalities described in the following detaileddescription.

As shown in FIGS. 1A and 1B, a breath actuated inhaler which is merelyan example of an inhaler in accordance with the present invention,includes a force holding unit or cap housing 12, a main body 14, amouthpiece dust cap 16 and a dose counter door 18 having a dose counterwindow 20.

As shown by the exploded view of FIG. 2, a dose counter chamber 22includes a dose counter system 24 closed within it by the dose counterdoor 18.

The dose counter system is shown in enlarged detail in FIG. 3 andincludes an actuating pin 26 and return spring 28. The dose counter cantake various forms and may, for example, be as described in EP2135199Aor EP2514464A.

As also shown in FIG. 2, the inhaler 10 includes a force holding unit 30which includes: a filter 32, flap valve housing 34, flap valve 36, flapvalve spring 38, main compression spring 40, retaining ring 42,diaphragm 44 and lower cap 46. The inhaler also includes a canister 50with a metering valve 52 and a valve stem 54; as well as a yoke 56 withdrive rods or legs 58 having distal ends 59 which are driven byrespective cams 60 on the hingedly-connected mouthpiece dust cap. Thevalve stem 54 is fitted into an inner bore 61 (FIG. 15B) of a valve stemblock 62 which communicates with a nozzle 64 for ejection of inhalablesubstances through a central bore 68 (FIG. 12) of a mouthpiece 66 (FIG.12 and FIG. 2) of the main body 14 of the inhaler 10.

The force holding unit 30 operates substantially as disclosed withreference to FIGS. 1 to 3 of EP1289589A and the yoke 56 and mouthpiecedust cap 16 substantially as described in EP2514465A, including but notlimited to FIG. 22 thereof.

In particular, with reference to FIGS. 5A to 5D, starting from aconfiguration in which the mouthpiece dust cap 16 is closed in thisconfiguration the liquid 201 in an interior reservoir 84 of canister 50communicates with a metering chamber 82 which does not communicate withatmosphere through an interior bore 88 of the valve stem 54. An openingrotation of the mouthpiece dust cap 16 to the configuration of FIGS. 6Ato 6D enables the distal ends 59 of the drive rods 58 and indeed thewhole yoke 56 to be moved away from the cap housing 12 under theinfluence of the main compression spring 40, the main compression spring40 being reacted against as equilibrium is reached for the canisterposition by friction forces as well as forces provided by partial vacuumat the diaphragm, the dose counter return spring 28, and metering valvespring 70 (FIG. 4) which forms part of the metering valve 52. In thisconfiguration, the metering chamber 82 is isolated from both of theinterior reservoir 84 and atmosphere.

As the next step, the user (not shown) inhales through the mouthpiece 66and the drawing out of air through the central bore 68 in turn draws airinto the enclosure formed by the main body 14 and cap housing 12 throughthe series of approximately ten air inlets 72 formed on the cap housing12. The incoming air impinges upon the flap 74 which releases vacuum(i.e. a partial vacuum) from the vacuum chamber formed by the diaphragm44 due to flap seal 76 rising off port 78 on diaphragm top plate 80.With the vacuum released, as shown in FIGS. 7A to 7D, as the user isinhaling air through the inhaler 10, i.e. through the apertures 72 andall of the way along inside the cap housing 12 and main body 14 past thecanister 50 and out through the central bore 68, the main compressionspring 40 drives the lower cap 46, yoke 56 and canister 50 away from thecap housing 12 and towards the main body 14 and valve stem block 62whereby the valve stem 54 is retracted into the canister 50. This placesthe pressurised metering chamber 82 in communication with valve stemblock nozzle 64 so fires the canister and ejects inhalable substancesfrom the metering chamber 82 through the nozzle 64 and mouthpiece 66towards the lungs (not shown) of the user. The dose counter system 24also registers a count by movement of the actuating pin 26 by thecanister ferrule 220. At this time after opening and firing, themetering chamber 82 communicates with atmosphere. With the mouthpiece 66left open such that the atmosphere communicates through the bore 88 andexit port 90 with the metering chamber 82, the metering chamber 82 canbecome at least partially or fully filled with gas such as air from theatmosphere.

In other embodiments comprising nasal inhalers, the mouthpiece 66 may bereplaced with a nose piece.

As shown in FIGS. 8A to 8D, during closing, the mouthpiece dust cap 16is rotated back to its closed position and the cams 60 push on thedistal ends 59 of the drive rods 58 so as to push the yoke 56 towardsthe cap housing 12 so as to compress the main compression spring 40again and the vacuum is formed again at the diaphragm 44. At the sametime, the canister is pushed back to its original configuration of FIGS.5A to 5D by the metering valve return spring 70.

As shown in FIG. 9, with the inhaler 10 in the configuration of FIGS. 5Ato 5D, the metering valve spring 70 keeps the valve stem 54 extended,the inlet port 86 open and the exit port 90 effectively closed, i.e.with the metering chamber 82 isolated from atmosphere. At the same timethe force F_(YL) applied as F_(YL)/2 by each of the legs or rods 58 ofthe yoke 56 to the lower cap 46 is greater than or equal to the forceF_(FHUCS) applied in the opposite direction by the spring of the forceholding unit 12.

As shown in FIG. 10, with the inhaler then changed to the configurationof FIGS. 6A to 6D, the canister is displaced to a representativedistance D_(valve) from the canister position of FIG. 9 where thisdisplacement at D_(valve) is less than the displacement required toactuate and fire a dose. In this FIG. 10 configuration, the position ofthe canister 50 is determined by an equilibrium between forces, whichis:

F _(valve CS) +F _(Dia) =F _(FHU CS)

where F_(valve CS) is the force applied to the canister by the meteringvalve spring 70, F_(Dia) is the force applied by the partial vacuum inthe diaphragm 44 in the same direction and F_(FHU CS) is the opposingforce applied by the compression spring 40 of the force holding unit 30.The port 78 is noted to be closed. The port 86 is open and the port 90is closed.

As the user then inhales, the port 78 is opened by the action of airentering through the apertures 72 impinging on the flap 74, lifting flapseal 76. The equilibrium of FIG. 10 is therefore lost. The canister 50is therefore moved to displace the valve stem 54 more, to theconfiguration of FIG. 11, so that the canister is a representativedistance D_(Actuated) from the valve stem block 62, and where the forcebalance is that F_(valve CS)≤F_(FHUCS) in which the force applied to thelower cap 46 is less than or equal to the opposing force applied by thecompression spring 40 of the force holding unit R. In thisconfiguration, the port 86 has closed to isolate the metering chamber 82from the interior reservoir 84 of the canister 50 and after this closurethe port 90 has opened, thereby firing the canister 50 by ventingpressurised contents within the metering chamber 82 out through thenozzle 64 of the valve stem block 62 for inhalation by the user.

The spring 40 is adapted such that the firing force F_(FHU CS) is morethan 35 N, typically less than 60 N. This may vary in other embodiments.

In most embodiments, the spring 40 is adapted in addition to devicegeometry such that the force exerted by the spring 40 on thevalve/canister is equal to the sum of the opposing valve spring 70 andpneumatic resistance force in the FHU diaphragm 44 in the preparedposition. Nonetheless, the spring 40, unless otherwise assisted, must beable to provide sufficient force once the mechanism is triggered toactuate the canister on inhalation. The specific force values will bedependent on the componentry of the device, driven predominately by theforce required to actuate the canister at a specific displacement, thusthe spring 40 will be adapted to suit.

The metering valve 52 shown in FIG. 4 is similar to those described inU.S. Pat. No. 7,959,042B, which is incorporated by reference herein, andhas the metering chamber 82 arranged for selective communication witheither the interior reservoir 84 of the canister 50 via an inlet port86, or with the interior bore 88 (FIGS. 5A to 5D) of the valve stem 54which communicates via the valve stem block 62 with the nozzle 64, thevalve stem 54 being provided with a radially configured capillary exitport 90 leading to the bore 88. The metering chamber 82 is at leastpartly defined by a cup-shaped inner metering body 92 and has an innerseal 94 and outer seal 96, as well as a location member 98, a maincanister seal 100 and a crenelated valve stem driver 102 which has athrough bore 104 axially directed towards the inlet port 86. The inletport 86 includes two elongate openings 106 diametrically opposed to oneanother and which are defined by a pair of forked legs 108 which arespaced apart from one another by the elongated openings 106 and the openspace forming the inlet port 86 between them. The forked legs 108 havesubstantially constant cross-section all the way along to their distalends (not shown) which are located within the crenelated valve stemdriver 102.

When the valve stem 54 is depressed into the canister 50 so that theinlet port 86 permits communication between the metering chamber 82 andthe interior reservoir 84, the communication into the interior reservoir84 is at an inner side 110 of the inner seal 94 and it will beappreciated that this is a slot-shaped porting between the forked legs108 from where flow can travel directly axially into our out of theinterior reservoir 84.

According to an alternative embodiment, the arrangement of openings inthe metering valve of the present invention is similar to thosedescribed in US2016/0084385, which is incorporated by reference herein.In particular, the metering valve of the present invention may besimilar to the embodiment shown in FIG. 4 of US2016/0084385, in whichthe valve body includes at least one first opening (i.e., at least onefirst side hole 100 that is arranged in a cylindrical portion of thevalve body) and at least one second opening (i.e., at least one secondside hole 111 that, as with the first hole(s), is arranged in acylindrical portion of the valve body), the second opening(s) beingaxially offset relative to the first opening(s) along a longitudinalaxis that extends between a first axial end and a second axial end ofthe valve body. The first opening(s) and second opening(s) that areaxially offset from each other along the valve body enable the meteringchamber to be filled and emptied.

The canister 50 includes inhalable substances including the activeingredient beclomethasone dipropionate and the propellant HFA134a whichhas a surface tension of about 8 mN/m as liquid at 25° C. Other activeingredients may be used in other embodiments, such as tiotropiumbromide.

If the mouthpiece dust cap 16 is left open such that the atmospherecommunicates through the bore 88 and exit port 90 with the meteringchamber 82, the metering chamber can become at least partly orsubstantially fully filled with gas such as air from the atmosphere.When the mouthpiece dust cap 16 is closed, however, and when theinterior reservoir 84 is oriented above the metering chamber 82, thepresent inventors have discovered that the liquid phase in the interiorchamber can exchange places with gas in the metering chamber 82, thefluid travelling either directly through the openings 106 or through thethroughbore 104, and along through the inner seal 94 and into themetering chamber 82 and gas in the metering chamber 82 can travel in thereverse direction along the same path, exiting with an axial componentthrough between the forked legs 108 and through the elongated openings106 into the interior reservoir 84. It is believed that the particularsurface tension of the chosen propellant promotes this action and thehigher density of the liquid than that of any gas in the meteringchamber enabling the latter to rise up in and relative to the liquid.

The full filling of the metering chamber 82 with a dose of liquid fromthe interior reservoir 84 with any gas in the metering chamber passingin the reverse direction from the metering chamber 82 into the interiorreservoir 84 is highly advantageous since with this one extension of thevalve stem 54 from its retracted configuration after inhalation to itsextended configuration with the mouthpiece dust cap 16 closed againensures that the inhaler 10 is fully primed for use. This has overcome asignificant problem.

As shown in FIG. 20, the inhaler 10 may be provided with a preventer 110for preventing the user from taking a second or further inhalation whilethe dust cap 16 is still open. The preventer 110 may take the form of awarning signaller 102 such as a warning notice as shown in the drawingstating “to reload: close before each inhalation” although in otherembodiments the preventer 110 could take various other forms such as analarm or audible or visual warning device to indicate that themouthpiece dust cap 16 is open and needs to be closed prior to the nextinhalation.

FIG. 21 is a graph showing a comparison of the inhaler of FIG. 1A withdelivered dose for a prior art breath actuated inhaler with a differentmetering valve (not shown) in which the exit port from the interiorreservoir comprises a radially oriented capillary bore which leads to aninternal bore of the valve stem leading axially towards a furtherradially extending capillary port, such that the communication from theinterior space is through the first capillary port, along the internalbore and out through the second radial capillary port into the meteringchamber when the valve stem is in its extended configuration. In allcases the inhalers were held with the valve stems vertical and thecanister interior reservoir above the metering chamber. Afterinhalation, the valve stem in each case was left in the retracted inhaleconfiguration with the metering chamber exposed to atmosphere throughthe valve stem for the specified delay period and the inhaler was thenreset and readied for inhalation, in the case of the present inhaler 10by closing and opening the mouthpiece cap again. As shown by the graphof FIG. 21, with a target of 80 micrograms of BDP (beclomethasonedipropionate) the diamond shaped plots 205 are for the prior art inhalerwhich began to fail to reach 75% of the labelled claim for the doseafter a delay of 30 seconds after inhalation in closing the mouthpiececap to isolate the metering chamber from atmosphere. At all delays of 2minutes or over, the prior inhaler failed to provide 75% of the labelledclaim of dose in 100% of cases. This, the present inventors havediscovered, is due to gas lock forming in the metering chamber afterinhalation due to the metering chamber's exposure to atmosphere, i.e. inthat when the mouthpiece cap is closed after a delay air is trapped inthe metering chamber and is not replaced by liquid in the interiorreservoir even when the metering chamber is connected to the interiorreservoir. In contrast, the plots of crosses 207 in FIG. 21 show theperformance of the inhaler of FIG. 1A. Here, 100% of the plots are inthe range of 75 to 125% of labelled claim for the dose, even when thereis no appreciable delay or a delay of one hour, twelve or twenty-fourhours before closing the mouthpiece cap after inhalation. Therefore,even if the metering chamber 82 has been exposed to atmosphere for arelatively long time such that it is after that delay substantially fullof gas due to evaporation/diffusion of substances after inhalation, thisgraph clearly shows that by closing the mouthpiece fully and opening itagain, the gas in the metering chamber 82 is removed into the interiorreservoir 84 and replaced with a correct dose very reliably.

Although FIG. 21 data is presented for 80 mcg (ex-actuator) targeted BDPHFA product, the data is representative of any formulation andformulation strength.

30 As shown in FIG. 12, the main body 14 has a tubular body portion 120arranged to contain the pressurised canister 50 for sliding motion. Asshown in FIG. 12, the valve stem block has a top surface 122 and thetubular body portion 120 has at least two mutually opposed guide ribs124, 126. The guide ribs 124, 126 have substantially straight guideedges 130, 132 extending parallel to and spaced from one another, eachstraight guide edge 130, 132 having an upper corner 134, 136 where thestraight guide edge meets a further surface 138, 140 of the ribs 124,126 leading outwardly towards an upper rib section near an inner wall146 of the tubular body portion 120. At least one of the ribs 124, 126has its straight guide edge's upper corner 134, 136 positioned adistance D2 in a direction parallel to an axis of the valve stem block62 along away from the top surface 122 of the valve stem block 62, adistance between the straight guide edges 130, 132 of the ribs 124, 126perpendicular to the axis being ID2, and the ratio D2 divided by ID2 is0.7. This is smaller than in previous embodiments and can surprisinglyassist in providing smooth guiding of the canister within the tubularbody portion 120.

The further surface 138, 140 of at least one of the guide ribs 124, 126and in this case both of them extends away from the valve stem block 62and terminates at a distance D3—in the case of guide rib 124—from thetop surface 122 of the valve stem block 62 in the direction parallel tothe axis, the ratio D3 divided by ID2 being 0.8, the equivalent ratiofor the guide rib 126 being 1.0. Each guide rib meets the upper ribsection 142, 144 near the inner wall 146 of the tubular body portion 120at an outer rib position 148, 150 wherein the outer rib positions are adistance apart ID1 in a direction perpendicular to the axis 202 of thevalve stem block 62 and the ratio ID2 divided by ID1 is 0.8. Thisarrangement assists beneficially in providing sufficient space for thecanister 50 to move within the tubular body section 120.

With reference to FIG. 13, a portion of the main body 16 is shown withthe mouthpiece dust cap 16 and the dose counter door 18 and the dosecounter system 24 not yet installed. As can be seen, the dose counterchamber 22 includes a recess 152 for location of an end 154 (FIG. 3) ofthe return spring 28. The recess 152 has a substantially flat reactionsurface for pushing on the end 154 of the return spring 28. The recess152 also has a shoulder surface 158 adjacent the reaction surface 156and an entrance mouth 160 into the reaction surface 156. A distinctguide surface 162, which is substantially planar is provided for guidingthe end 154 of the return spring 28 into the recess 152 during assembly.The distinct guide surface 162 is wider than the entrance mouth 160 in adirection across the mouth and this assists substantially in assemblingthe spring 28 into the recess 152.

The entrance mouth 160 also has at least a chamfered entrance lip 164,an extension 166 of which into the guide surface forms a slanted edge166 of the distinct guide surface 162. At least a portion of thedistinct guide surface 162 comprises a portion of the body 14 which isrecessed relative to the adjacent and partially surrounding portion 164of the body by an edge 168. The edge 168 is particularly effective incatching the end 154 of the return spring and the wide guide surface 162is effective in guiding the spring 28 past the chamfered entrance lip164 and onto the reaction surface 156 where it remains once installed. Afurther edge 170 of the guide surface 162 is spaced from and generallyparallel to the edge 168. The edge 170 forms an intersection with anadjacent portion 171 of the body 14.

As shown in FIG. 14A, the main body of the inhaler 10 includes a barrier180 separating an interior space 182 defined at least partly by thetubular body portion 120 from the dose counter chamber 22. The barrierincludes a stepped upper wall area 184 which has four steps 186, 188,190, 192 at different levels. The steps are arcuate and havesubstantially flat parts 194, 196, 198, 200 aligned substantiallyperpendicular to the axis 202 of the valve stem block as well apart-cylindrical risers 204, 206, 208 between the substantially flatparts 194, 196, 198, 200.

The arcuate steps 186, 188, 190, 192 are substantially concentric withthe axis 202 of the valve stem block 62. The steps 186, 188, 190, 192extend around the valve block 62 a distance/angle of about 170° althoughthis is only approximate and may be in the region of about 180 to 120°in various embodiments. The material forming the barrier 180 is ofsubstantially constant thickness throughout the steps 186, 188, 190, 192which is advantageous for manufacturing techniques by moulding.

As shown in FIG. 14B which is a view into the dose counter chamber 22,the dose counter chamber 22 is formed with two heat staking pins 212,214 for attaching the dose counter system 24 permanently into positionwithin the dose counter chamber 22. One of the heat staking pins 214 isdirectly attached to two of the steps 188, 190. The heat staking pin 214is attached to one substantially flat step part 198 and to two steprisers 206, 208, providing secure and advantageous location of the heatstaking pin 214 in the stepped upper wall area 184 of the barrier 180.An aperture 218 for the actuating pin 26 of the dose counter system 24is formed through the second furthest step part 198 away from the valvestem block 62.

The stepped upper wall area 184 is highly advantageous since it enablesthe accommodation of a length of movement of the canister 50 and inparticular its ferrule 220 (FIG. 2) within the main body 14. Therefore,even with a metering valve 70 as used in the inhaler 10 which has arelatively long end-to-end travel of approximately 4 mm, the internalcomponents can be maintained within a relatively small and compactinhaler 10, while also allowing for space in the dose counter chamber 22for the dose counter system 24 and enabling the dose counter to be heatstaked firmly in place by the heat stake pins 212, 214 including the pin214 which is attached to the stepped upper wall area 84 of the barrier180.

As shown in FIGS. 15A and 15B, the valve stem block 62 has thecylindrical inner bore 61 which has an inner diameter BD1 which has afirst diameter, a seal 224 at an entrance to the inner bore 61 having asecond diameter BD2 which is smaller than the first diameter. The seal224 is inwardly convex and/or is toroidal. The first diameter BD1 isabout 3.22 mm and is about 3.5% larger than the second diameter BD2. Thevalve system 54 has a cylindrical outer surface 226 (FIG. 2) with adiameter which is smaller than the first diameter BD1 but larger thanthe second diameter BD2 prior to introduction of the valve stem 54 intothe inner bore 61 and is about 1% larger. The valve stem block 62 alsoincludes an annular recess 228 which extends more than half way aroundthe periphery of the inner bore 61, in this embodiment about 350° ormore. The annular recess 228 has an inner diameter which is about 40%larger than the inner diameter BD1 of the cylindrical inner bore 61.This arrangement has been found to provide extremely effective sealingagainst blowback which has occurred in prior designs which have asubstantially greater interference fit between the exterior diameter ofthe valve stem and the interior diameter of the inner bore of the valvestem. Surprisingly, and advantageously, using the inwardly convex seal224 to the bore 61, very effective sealing without any blowback can beachieved even with a relatively small interference fit between the valvestem 54 and the seal 224, the annular recess 228 assisting in providingresilience to the valve stem block 62 for this purpose. The smallinterference fit allows for good sealing even when the inhaler 10 issubjected to high temperatures for long periods since there is littlestress to relieve. Furthermore, the seal 224 permits a relatively lowinsertion force for inserting the valve stem 54 into the valve stemblock 62 and this enables accurate positioning of these two componentsrelative to one another in an axial direction of the valve stem 54 sothat the dose counter system 24 can count reliably by way of accurateactuation of its actuator pin 26 by the canister ferrule 220.

As shown in the various sectional views of FIGS. 16A through to 18C, alock system 250 is provided for locking the cap housing or force holdingunit housing 12 on the main body 14. Helical threads 252, 254 areprovided, with male threads 252 on the cap housing 12 and female threads254 on the main body 14, for rotational attachment of the cap housing 12on the main body 14 and for resisting relative longitudinal movementtherebetween without rotation.

The lock system 250 includes a protrusion 256 in the region of thehelical thread 254 on the main body 14 which is lockable in a recess 258in the region of the helical thread 252 on the cap housing. As shown inFIG. 17C, the inhaler 10 includes two of the protrusions 256 in two ofthe recesses 258 formed at opposing locations on the inhaler, i.e.diametrically opposite to one another. As shown in FIG. 18A, eachprotrusion 256 has a leading ramp surface 260 and a trailing rampsurface 266, the included angle A between the ramp and trailing surfaces260, 266 being 115°, although a range of about 95 to 120° is envisaged.The recesses have a similar included angle which is smaller than theangle of the protrusion 256 at about 100°. This ensures that theprotrusion 256 will fit securely in the recess 258 without any playrotationally.

The main body 14 has a central axis 202 coincident with that 202 of thevalve stem block 62 and the ramp surfaces 266 are inclined at an angleof about 45°±15° to tangential.

The lock system 250 also includes a first lock member 270 on the caphousing 12 which is adapted to engage a second lock member 272 at a lockinterface 274 formed by respective engagement faces thereof, the lockinterface 274 being oriented substantially perpendicular to tangential.This therefore assists in preventing rotation. The first lock member 270has a radial extent of 0.39 mm, although about 0.35 to 0.45 mm isenvisaged in other embodiments or 0.25 to 0.75 mm. The second lockmember 272, it will be appreciated, has a greater radial extent. Thefirst lock member 270 has a longitudinal extent parallel to the axis 202of about 10 mm.

The main body 14 and cap housing 12 are formed of plastics material andthe lock system 250 is configured so that a release torque required toovercome the locking provided by the plastics main body and cap housingat the lock interface 274 and at the protrusions 256 and recesses 258 ismore than 1 Nm. In the described example, the release torque is about2.75 Nm. When an information sticker is applied over the top of theinterface between the main body 14 and cap housing 12 the release torquemay rise to about 3.5 Nm. This has been found to be lower than 4 Nm andthis is low enough that a laboratory is capable of opening up theinhaler 10 for inspection without significant destruction. However, thislevel of torque is significantly higher than likely to be tried by auser in an attempt to open the inhaler 10 which might result intampering and damage to the components of the inhaler 10.

In an alternative design, the radial extent of the first locking member270 is significantly greater at about 0.73 mm and this has been found,surprisingly, to provide a removal torque which is considered too highat 4.6 Nm for laboratory disassembly without destruction. In contrast, adesign omitting the first lock member 270 was found to provide a removaltorque of only 0.7 Nm which is considerably too low and likely to resultin users rotating the cap housing 12 off the main body 14 andpotentially damaging the inhaler by investigating the contents. In fact,this was the first design attempted by the present inventors and thenext step was to double up the number of protrusions 256 and recesses258 so that there are four in total in an attempt to double the torque,at least, from 0.7 Nm. However, surprisingly, with this design, theremoval torque was only increased by about 10% to 0.8 Nm. The idealremove torque was surprisingly achieved with only one protrusion 256 oneach thread 254 and with a locking member 270 with only a small radialextent of 0.39 mm. The locking member 270 advantageously also includes alead ramp 290 for achieving a smooth snap lock of the cap housing 12onto the main body 14 when the cap housing 12 is twisted into the lockedposition.

FIG. 19 shows a modification of the inhaler 10 to form an inhaler 1000which is a metered dose inhaler having a main body 1002 and mouthpiecedust cap 1004 for the mouthpiece 1006 for stopping foreign objectsentering the central bore 1008 of the mouthpiece 1006 and for protectingthe mouthpiece generally. This metered dose inhaler 1000 does notinclude the cap housing 12 or the force holding unit 30 or yoke 56 butit does include the same dose counter chamber 22, dose counter system24, canister 50 and metering valve 52 and valve stem 54 and valve stemblock 62 as that in the inhaler 10. If this metered dose inhaler is leftwith the canister 50 accidentally depressed, for example while squashedin luggage or clothing by mistake, such that the metering chamber isleft exposed to the atmosphere for a considerable period of time, thenwhen the inhaler 1000 is located and turned upright for use withrespective gravity with the canister allowed to extend to its restposition in which the metering chamber communicates with the interiorreservoir, any gas such as air which has entered the metering chamber iseasily expelled up into the interior reservoir of the canister just asin the inhaler 10 such that an accurate next dose is applied and theproblem of gas lock is therefore avoided.

Inhalers in accordance with preferred embodiments of the presentinvention are suitable for the delivery of many classes of activeingredients by inhalation, and may be used for the treatment of variousdiseases and disorders. According to preferred embodiments, the inhaleris used for the treatment of respiratory disorders (e.g., COPD, asthmaand/or cystic fibrosis). The inhaler may also be used to treatnon-respiratory disorders, such as migraine. According to an embodiment,a method of treating a respiratory disease or disorder comprisesactuating the inhaler to administer a therapeutically effective amountof one or more active ingredients. As described herein, the canister ofthe inhaler contains a drug formulation comprising one or more activeingredients in suspension or in solution. Preferably, the drugformulation comprises one or more active ingredients in propellant(e.g., HFA). The drug formulation may optionally comprise one or moreexcipients in combination with the active ingredient(s) and propellant.

In certain embodiments, the inhaler described herein can be used totreat patients suffering from a disease or disorder selected fromasthma, chronic obstructive pulmonary disease (COPD), exacerbation ofairways hyper reactivity consequent to other drug therapy, allergicrhinitis, sinusitis, pulmonary vasoconstriction, inflammation,allergies, impeded respiration, respiratory distress syndrome, pulmonaryhypertension, pulmonary vasoconstriction, and any other respiratorydisease, condition, trait, genotype or phenotype that can respond to theadministration of, for example, a long-acting muscaric antagonist(LAMA), long-acting β2-adrenergic agonist (LABA), corticosteroid, orother active agent as described herein, whether alone or in combinationwith other therapies. In certain embodiments, the compositions, systemsand methods described herein can be used to treat pulmonary inflammationand obstruction associated with cystic fibrosis. As used herein, theterms “COPD” and “chronic obstructive pulmonary disease” may encompasschronic obstructive lung disease (COLD), chronic obstructive airwaydisease (COAD), chronic airflow limitation (CAL) and chronic obstructiverespiratory disease (CORD) and include chronic bronchitis,bronchiectasis, and emphysema. As used herein, the term “asthma” refersto asthma of whatever type or genesis, including intrinsic(non-allergic) asthma and extrinsic (allergic) asthma, mild asthma,moderate asthma, severe asthma, bronchitic asthma, exercise-inducedasthma, occupational asthma and asthma induced following bacterialinfection. Asthma is also to be understood as embracing wheezy-infantsyndrome.

A range of classes of active ingredients have been developed to treatrespiratory disorders and each class has differing targets and effects.

Bronchodilators are employed to dilate the bronchi and bronchioles,decreasing resistance in the airways, thereby increasing the airflow tothe lungs. Bronchodilators may be short-acting or long-acting.Typically, short-acting bronchodilators provide a rapid relief fromacute bronchoconstriction, whereas long-acting bronchodilators helpcontrol and prevent longer-term symptoms.

Different classes of bronchodilators target different receptors in theairways. Two commonly used classes are anticholinergics and β2-agonists.

Anticholinergics (or “antimuscarinics”) block the neurotransmitteracetylcholine by selectively blocking its receptor in nerve cells. Ontopical application, anticholinergics act predominantly on the M3muscarinic receptors located in the airways to produce smooth musclerelaxation, thus producing a bronchodilatory effect. Non-limitingexamples of long-acting muscarinic antagonists (LAMA's) includetiotropium (bromide), oxitropium (bromide), aclidinium (bromide),ipratropium (bromide) glycopyrronium (bromide), oxybutynin(hydrochloride or hydrobromide), tolterodine (tartrate), trospium(chloride), solifenacin (succinate), fesoterodine (fumarate),darifenacin (hydrobromide) and umeclidinium (bromide). In each case,particularly preferred salt/ester forms are indicated in parentheses.

β2-Adrenergic agonists (or “β2-agonists”) act upon the β2-adrenoceptorsand induce smooth muscle relaxation, resulting in dilation of thebronchial passages. Non-limiting examples of long-acting β2-adrenergicagonists (LABA's) include formoterol (fumarate), salmeterol (xinafoate),indacaterol (maleate), bambuterol (hydrochloride), clenbuterol(hydrochloride), olodaterol (hydrochloride), carmoterol (hydrochloride),tulobuterol (hydrochloride) and vilanterol (triphenylacetate).Non-limiting examples of short-acting β2-agonists (SABA's) includealbuterol (sulfate) and levalbuterol (tartrate). In each case,particularly preferred salt/ester forms are indicated in parentheses.

According to one embodiment, the formulation comprises albuterol(sulfate).

Another class of active ingredients employed in the treatment ofrespiratory disorders are inhaled corticosteroids (ICS's). ICS's aresteroid hormones used in the long-term control of respiratory disorders.They function by reducing the airway inflammation. Non-limiting examplesof inhaled corticosteroids include budesonide, beclomethasone(dipropionate), fluticasone (propionate), mometasone (furoate),ciclesonide and dexamethasone (sodium).

According to one embodiment, the formulation comprises beclomethasonedipropionate.

According to an embodiment, the inhaler delivers one or more activeingredients selected from the group consisting of tiotropium (bromide),oxitropium (bromide), aclidinium (bromide), ipratropium (bromide)glycopyrronium (bromide), oxybutynin (hydrochloride or hydrobromide),tolterodine (tartrate), trospium (chloride), solifenacin (succinate),fesoterodine (fumarate), darifenacin (hydrobromide), umeclidinium(bromide), formoterol (fumarate), salmeterol (xinafoate), indacaterol(maleate), bambuterol (hydrochloride), clenbuterol (hydrochloride),olodaterol (hydrochloride), carmoterol (hydrochloride), tulobuterol(hydrochloride), vilanterol (triphenylacetate), albuterol (sulfate),levalbuterol (tartrate), budesonide, beclomethasone (dipropionate),fluticasone (propionate), mometasone (furoate), ciclesonide,dexamethasone (sodium) and a combination thereof.

According to particular embodiments, the inhaler delivers a combinationof at least two different active ingredients (two, three, four, etc.)which belong to the same or different classes. According to oneembodiment, the inhaler delivers a “triple combination” of threedifferent active ingredients. The three active ingredients may belong tothree different active ingredient classes (e.g., LAMA, LABA, ICS);alternatively, two or three of the active ingredients may belong to thesame class.

According to additional embodiments, the inhaler delivers one or moreactive ingredients selected from the group consisting of a long-actingmuscarinic antagonist (LAMA), a long-acting β2-adrenergic agonist(LABA), an inhaled corticosteroid (ICS) and a combination thereof. Thus,the inhaler may deliver a formulation comprising one or more LAMA's, oneor more LABA's and one or more ICS's. That is, the device may deliver adouble combination of a LAMA and a LABA, a LAMA and an ICS, or a LABAand an ICS; or a triple combination of a LAMA, a LABA and an ICS.

According to an alternative embodiment, the inhaler delivers one or moreactive ingredients for the treatment of a headache disorder, such asmigraine. For example, the inhaler may deliver dihydroergotamine (DHE)or a pharmaceutically acceptable salt thereof, such as dihydroergotaminemesylate.

In one embodiment the inhaler comprises a reservoir, particularly apressurized canister, comprising an active ingredient.

Preferably the active ingredient is presented in a pharmaceuticalformulation comprising a propellant, optionally a co-solvent andoptionally other pharmaceutically acceptable excipients.

Preferred propellants include hydrofluroalkanes, in particular1,1,1,2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-heptafluoropropane(HFA227), or combinations thereof. Most particular propellant isHFA134a. Most particular HFA134a concentration is from about 91.8% w/wto 92.9% w/w.

HFA134a has a low boiling point (−26.1° C.) and correspondingly highvapor pressure (572 kpa) at 20° C.

Particular co-solvents are selected from the list of aliphatic alcohols(particularly ethanol), glycerols and glycols. Most particularco-solvent is ethanol. Most particular ethanol concentration is about 8%w/w.

Ethanol is well known to be compatible with HFA-134a and increases thesolubility of BDP. Ethanol (anhydrous) is used as a co-solvent to aidsolubility of BDP in HFA134a. A concentration of around 8% w/w ofethanol is known to provide necessary stability, preventingprecipitation and achieving correct aerosol performance.

Other pharmaceutically acceptable excipients include surfactants,particularly oleic acid. Preferably, the active ingredient is suspendedin the propellant. Alternatively the active ingredient is dissolved inthe propellant. The active ingredient may also be partly suspended andpartly dissolved in the propellant.

A particular active ingredient is selected from the group consisting ofanti-inflammatory agents, β2-adrenoreceptor agonists, anti-cholinergicagents, anti-histamines, serotonin agonists, and combinations thereof.

A particular corticosteroid is beclomethasone dipropionate (BDP).

A particular β2-adrenoreceptor agonist is salbutamol sulphate.

In a particular embodiment of the invention, the active ingredient isselected from beclomethasone dipropionate (BDP), salbutamol sulphate anddihydroergotamine.

In a particular embodiment the inhaler comprises a pressurized canistercomprising beclomethasone dipropionate as active ingredient, HFA134a aspropellant and ethanol as co-solvent.

In a particular embodiment the inhaler comprises a pressurized canistercomprising beclomethasone dipropionate as active ingredient at about 1.0mg/ml, HFA134a as propellant at about 1090.20 mg/ml and ethanol asco-solvent at about 94.80 mg/ml.

In a particular embodiment the inhaler comprises a pressurized canistercomprising beclomethasone dipropionate as active ingredient at about0.084% w/w, HFA134a as propellant at about 91.9% w/w and ethanol asco-solvent at about 8.0% w/w.

In a particular embodiment the inhaler comprises a pressurized canistercomprising beclomethasone dipropionate as active ingredient at about0.169% w/w, HFA134a as propellant at about 91.8% w/w and ethanol asco-solvent at about 8.0% w/w.

In a particular embodiment the inhaler comprises a pressurized canistercomprising salbutamol sulphate as active ingredient, HFA134a aspropellant and ethanol as co-solvent.

In a particular embodiment the inhaler comprises a pressurized canistercomprising about 0.1098 mg of salbutamol sulphate as active ingredient,about 27.8 mg of HFA134a as propellant and about 3.6 mg of ethanol asco-solvent.

One embodiment relates to an inhaler as described herein comprising anactive ingredient.

One embodiment relates to an inhaler as described herein comprising anactive ingredient for therapeutic use.

One embodiment relates to an inhaler as described herein comprising anactive ingredient for use in the treatment or prevention of arespiratory disease, particularly COPD or Asthma.

One embodiment relates to an active ingredient for use in the treatmentor prevention of a respiratory disease, particularly COPD or Asthma,wherein the active ingredient is delivered to a patient using an inhaleras described herein.

One embodiment relates to a method for the treatment or prevention ofrespiratory diseases, particularly COPD or Asthma, which methodcomprises administering an active ingredient to a human being or animalusing an inhaler as described herein.

One embodiment relates to the use of an inhaler as described hereincomprising an active ingredient for the treatment or prevention ofrespiratory diseases, particularly COPD or Asthma.

Embodiments of the present invention may be further understood byreference to the Example provided below.

EXAMPLE

According to the following example, a method of using the inhaler of thepresent invention comprises delivering a therapeutically effectiveamount of beclomethasone dipropionate HFA for the treatment of asthma,particularly for the maintenance treatment of asthma as prophylactictherapy in patients 4 years of age and older, wherein the inhaler is abreath-actuated inhaler (BAI) as described herein and the step ofactuating the inhaler comprises inhaling through the inhaler. Thebreath-actuated inhaler may be used by patients to deliver at leastabout 40 mcg beclomethasone dipropionate upon each actuation, preferablytwice daily, e.g., it may be used by patients 4 to 11 years old todeliver 40 mcg or 80 mcg beclomethasone dipropionate twice daily, or maybe used by patients 12 years of age and older to deliver 40 mcg, 80 mcg,160 mcg or 320 mcg beclomethasone dipropionate twice daily. Actuation ofthe breath-actuated inhaler is preferably triggered by an inspiratoryflow rate of at least about 20 liters per minute (L/min), and includes aprimeless valve so that no priming actuations are required before use. Amethod of treating asthma may comprise inhaling through the BAI at aflow rate of at least about 20 L/min without priming the inhaler beforeuse, wherein the inhaler comprises a primeless valve as described hereinand wherein the mean change from baseline for FEV₁ between 2-6 weeks orbetween 2-12 weeks or between 4-12 weeks of using the BAI is greaterthan about 0.150 L or greater than about 0.200 L. Preferably, the meanpeak plasma concentration (Cmax) of BDP is between about 6000 pg/mL andabout 7000 pg/mL or between about 6200 pg/mL and about 6800 pg/mL at 2minutes after inhalation of 320 mcg using the BAI (4 inhalations of the80 mcg/inhalation strength). The mean peak plasma concentration of themetabolite 17-BMP is preferably between about 1000 pg/mL and about 2000pg/mL or between about 1200 pg/mL and about 1700 pg/mL at 10 minutesafter inhalation of 320 mcg of the BAI.

The breath-actuated inhaler (BAI) in this example included a canisterhaving an interior reservoir containing pressurised inhalable substancesincluding fluid; a “primeless” metering valve including a meteringchamber and a valve stem defining a communication path between themetering chamber and the interior reservoir, the communication pathincluding an opening configured to permit flow between a transfer spaceinside the valve stem and the interior reservoir, the interior reservoirbeing arranged for orientation above the metering chamber whereby gassuch as air located within the metering chamber is replaced with liquidfrom the interior reservoir. Preferably, the primeless metering valve isthe embodiment shown in FIG. 4 and described in U.S. Pat. No.7,959,042B. Alternatively, the primeless metering valve is similar tothe embodiment shown in FIG. 4 of US2016/0084385, as described herein.

Two confirmatory Phase 3 clinical trials were conducted comparing theabove-described breath-actuated inhaler with placebo in adult andadolescent patients with persistent asthma (Trial 1 and Trial 2).

Trial 1: This randomized, double-blind, parallel-group,placebo-controlled, 12-week, efficacy and safety trial compared thebreath-actuated inhaler 40 and 80 mcg given as 1 inhalation twice dailywith placebo in adult and adolescent patients with persistentsymptomatic asthma despite low-dose inhaled corticosteroid ornon-corticosteroid asthma therapy. Patients aged 12 years and older whomet the entry criteria including FEV₁ 40-85 percent of predicted normal,reversible bronchoconstriction of 15% with short-acting inhaledbeta-agonist entered a 14-21 day run-in period. 270 patients (104previously treated with inhaled corticosteroids) who met all therandomization criteria including asthma symptoms and rescue medicationuse were discontinued from asthma maintenance medication and randomizedequally to treatment with the breath-actuated inhaler (BAI) 80 mcg/dayBDP, the breath-actuated inhaler 160 mcg/day BDP or placebo. BaselineFEV₁ values were similar across treatments. The primary endpoint forthis trial was the standardized baseline-adjusted trough morning forcedexpiratory volume in 1 second (FEV₁) area under the effect curve fromtime zero to 12 weeks [FEV₁ AUEC(0-12 wk)]. Patients in both treatmentgroups had significantly greater improvements in trough FEV₁ compared toplacebo (BAI 80 mcg/day, LS mean change of 0.124 L and BAI 160 mcg/day,LS mean change of 0.116 L over 12 weeks). In addition, the mean changefrom baseline for FEV₁ was greater than about 0.150 L between week 4through week 12 (generally between about 0.150 L and about 0.250 L).Both doses of BAI were effective in improving asthma control withsignificantly greater improvements in FEV₁ and morning PEF when comparedto placebo. Reduction in asthma symptoms was also supportive of theefficacy of the BAI.

Trial 2: This randomized, double-blind, parallel-group,placebo-controlled, 6-week, efficacy and safety trial compared BAI 40and 80 mcg BDP given as 4 inhalations twice daily and placebo in adultand adolescent patients with persistent symptomatic asthma despitetreatment with non-corticosteroid, inhaled corticosteroids (with orwithout a long acting beta agonist [LABA]), or combination asthmatherapy. The study also included a reference treatment group, QVAR®Inhalation Aerosol (QVAR MDI) 40 mcg, 4 inhalations twice daily.Patients aged 12 years and older who met the entry criteria includingFEV₁ 50-90% predicted normal, reversible bronchoconstriction of at least10% with short-acting inhaled beta-agonist discontinued baseline asthmatreatment and entered a 2-4 week run-in period. 425 patients (257previously treated with ICS with or without LABA) who met all therandomization criteria including FEV₁ of 40-85% predicted and 15%reversibility with short-acting inhaled beta-agonist, and asthmasymptoms were randomized equally to the BAI 320 mcg/day, BAI 640mcg/day, QVAR MDI 320 mcg/day or placebo. Baseline FEV₁ values weresimilar across treatments. The primary endpoint for this trial was thestandardized baseline-adjusted trough morning forced expiratory volumein 1 second (FEV₁) area under the effect curve from time zero to 6 weeks[FEV₁ AUEC(0-6 wk)]. Patients in both treatment groups had significantlygreater improvements in trough FEV₁ compared to placebo (BAI 320mcg/day, LS mean change of 0.144 L and BAI 640 mcg/day, LS mean changeof 0.150 L over 12 weeks). Treatment with QVAR MDI was similar. Thechange from baseline in morning FEV₁ during the trial was greater than0.150 L or 0.200 L between week 2 through week 6 (generally betweenabout 0.150 L and about 0.250 L). Both doses of the BAI were effectivein improving asthma control with significantly greater improvements inFEV₁, morning PEF, weekly average of daily trough morning FEV₁, reducedrescue medication use and improved asthma symptom scores than withplacebo. Similar results were demonstrated with QVAR MDI.

The inhaler of the present disclosure has broad application. Theapparatuses and associated methods in accordance with the presentdisclosure have been described with reference to particular embodimentsthereof in order to illustrate the principles of operation. The abovedescription is thus by way of illustration and not by way of relativeand directional references (including: upper, lower, upward, downward,left, right, leftward, rightward, top, bottom, side, above, below,front, middle, back, vertical, horizontal, height, depth, width, and soforth) are normally given by way of example to aid the reader'sunderstanding of the particular embodiments described herein. Theyshould not be read to be requirements or limitations, particularly as tothe position, orientation, or use of the invention unless specificallyset forth in the claims. Connection references (e.g., attached, coupled,connected, joined, secured and the like) are to be construed broadly andmay include intermediate members between a connection of elements andrelative movement between elements. As such, connection references donot necessarily infer that two elements are directly connected and infixed relation to each other, unless specifically set forth in theclaims.

Various modifications may be made to the embodiments described withoutdeparting from the scope of the invention as defined by the accompanyingclaims.

What is claimed is:
 1. An inhaler housing for an inhaler for inhalablesubstances, the inhaler housing being arranged to contain a pressurisedcanister for sliding motion within a tubular body portion thereof, theinhaler housing having a valve stem block for connection to a valve stemof a pressurised canister, the valve stem block having a top surface,the tubular body portion having at least two mutually opposed guide ribsfor guiding canister position within the tubular body portion, the guideribs having substantially straight guide edges extending substantiallyparallel to and spaced from one another, each straight guide edge havingan upper corner where the straight guide edge meets a further surface ofthe rib leading outwardly towards an upper rib section near an innerwall of the tubular body portion, at least one of the ribs having itsstraight guide edge's upper corner positioned a distance D2 in adirection parallel to an axis of the valve stem block along away fromthe top surface of the valve stem block, a distance between the straightguide edges of the ribs perpendicular to the axis being ID2, and inwhich the ratio D2/ID2 is less than 0.8.
 2. The inhaler housing of claim1 in which the ratio D2/ID2 is less than 0.75, about 0.7 being oneexample.
 3. The inhaler housing of claim 1 in which the further surfaceof at least one guide rib extends away from the valve stem block andterminates at a distance D3 from the top surface of the valve stem blockin the direction parallel to the axis, the ratio D3/ID2 being less than0.9 or less than 0.85, about 0.8 being one example.
 4. The inhalerhousing of claim 1 in which each guide rib meets the upper rib sectionnear the inner wall of the tubular body portion at outer rib positionswherein the outer rib positions are a distance ID1 apart in a directionperpendicular to the axis, and in which the ratio ID2/ID1 is between 0.7and 0.9, typically between 0.75 and 0.85, about 0.78 or 0.8 being twoexamples.
 5. An inhaler housing for an inhaler for inhaling inhalablesubstances, the inhaler having: a body and a dose counter with anactuation member adapted to drive a dose indication portion of the dosecounter against a return spring, the body including a recess forlocation of an end of the return spring; the recess having asubstantially flat reaction surface, a shoulder surface adjacent thereaction surface and an entrance mouth into the reaction surface;wherein a distinct guide surface is provided for guiding the end of thereturn spring into the recess, the distinct guide surface being widerthan the entrance mouth in a direction across the mouth.
 6. The inhalerhousing of claim 5 in which the entrance mouth has at least onechamfered entrance lip, the distinct guide surface having a slanted edgewhich is an extension of the lip.
 7. The inhaler housing of claim 5 inwhich the distinct guide surface is substantially coplanar.
 8. Theinhaler housing of claim 5 in which at least a portion of the distinctguide surface comprises a portion of the body which is recessed relativeto an adjacent portion of the body.
 9. An inhaler housing for an inhalerfor inhaling inhalable substances, the inhaler housing having a tubularportion defining a tubular interior space for containing a pressurisedcanister containing inhaler substances, a valve stem block forengagement with a valve stem of such a pressurised canister, and a dosecounter chamber for containing a dose counter assembly, the dose counterchamber being separated from the tubular interior space by a barrier,the barrier including a stepped upper wall area including at least threesteps at different levels.
 10. The inhaler housing of claim 9 whichincludes four said steps.
 11. The inhaler housing of claim 9 in whichthe steps are arcuate.
 12. The inhaler housing of claim 11 in which thearcuate steps have substantially flat areas aligned substantiallyperpendicular to an axis of the valve stem block as well aspart-cylindrical riser surfaces between the substantially flat areas.13. The inhaler housing of claim 11 in which the steps are substantiallyconcentric with an axis of the valve stem block.
 14. The inhaler housingof claim 11 in which the steps extend around the valve stem block adistance of about 180 degrees.
 15. The inhaler housing of claim 11 inwhich the material forming the barrier is of substantially constantthickness substantially throughout the steps.
 16. The inhaler housing ofclaim 11 in which the dose counter chamber is formed with at least oneheat staking pin for mounting of a dose counter system, the heat stakingpin being directly attached to at least two of the steps.
 17. Theinhaler housing as claimed in claim 16 in which the heat staking pin isattached to at least one step surface that is oriented substantiallyperpendicular to an axis of the valve stem block and to at least one andpreferably two step risers.
 18. The inhaler housing of claim 1 in whichan aperture for a drive pin for actuating the dose counter is formedthrough a second furthest step away from the valve stem block.
 19. Anapparatus comprising an inhaler valve stem and valve stem blockinterface for a breath actuated inhaler having a dose counter and apressurised canister containing inhaler substances including amedicament, which may be in suspension or in solution, the valve stemblock having a cylindrical inner bore with an inner diameter which is afirst diameter, the cylindrical inner bore being for accepting a valvestem with an outer diameter, the valve stem block having a seal in theinner bore with a second diameter which is smaller than the firstdiameter.
 20. The apparatus of claim 19 in which the first diameter isabout 3.22 mm.
 21. The apparatus of claim 19 in which the first diameteris about 3.5% larger than the second diameter.
 22. The apparatus ofclaim 19 in which an outer diameter of the valve stem is smaller thanthe first diameter but larger than the second diameter prior tointroduction of the valve stem into the inner bore, preferably about0.75% to 1.5% larger, for example about 1% larger.
 23. The apparatus ofclaim 19 in which the valve stem block includes an annular recessconcentric with and extending around the inner bore at least partiallyaround the circumference thereof, the inner diameter of the annularrecess being about 25 to 50% larger than the inner diameter of thecylindrical inner bore, for example about 40% larger.
 24. A breathactuated inhaler having a drive adapted to drive a pressurised canisterso as to retract a metering valve stem into the canister to fire thecanister, the canister being adapted to move during operation between 1and 4 mm between end positions of its length of travel relative to thevalve stem, the drive being arranged to apply a firing force of between15N and 60N of force to the canister at a position of the canisterrelative to the valve stem at which the canister fires.
 25. The breathactuated inhaler of claim 24 in which the drive comprises a drivespring.
 26. The breath actuated inhaler of claim 24 in which thecanister is arranged to move between 1 and 3 mm between the endpositions, for example 3 mm.
 27. The breath actuated inhaler of claim 24in which the drive is adapted to provide the firing force as more than25N, preferably also less than 60N.
 28. The breath actuated inhaler ofclaim 24 in which the firing force is more than 35N or equal to thatrequired to fire the canister.
 29. The breath actuated inhaler of claim24 in which the firing force is greater than the sum at the point offiring of opposing forces applied to the canister by a valve stem springin the canister and a return spring for an actuator pin of a dosecounter of the inhaler.
 30. An inhaler including the inhaler housing ofclaim
 1. 31. A method of treating a respiratory disease or disordercomprising actuating the inhaler of claim 24 to administer atherapeutically effective amount of one or more active ingredients. 32.The method of claim 31, wherein the inhaler is a breath-actuated inhalerand the step of actuating the inhaler comprises inhaling through theinhaler.
 33. The method of claim 31, wherein the respiratory disease ordisorder is asthma.
 34. The method of claim 31, wherein the respiratorydisease or disorder is COPD.
 35. The method of claim 31, wherein the oneor more active ingredients comprise a corticosteroid.
 36. The method ofclaim 31, wherein the one or more active ingredients comprisebeclomethasone dipropionate or tiotropium bromide.